Intestinal Mechanisms and Molecular Predictors of Type 2 Diabetes Remission After Roux-en-Y Gastric Bypass Surgery

Roux-en-Y 胃绕道手术后 2 型糖尿病缓解的肠道机制和分子预测因素

基本信息

批准号：
10161057
负责人：
Nicholas Stylopoulos
金额：
$ 15.98万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161057
关键词：
Address Affect Amino Acids Anatomy Animal Model Animals Applications Grants Award Basic Science Biology Biopsy Body Weight decreased Calories Carbon Case-Control Studies Cells Clinical Clinical Research Clinical Trials Data Data Set Development Diabetes Mellitus Disease Disease remission Early treatment Effectiveness Evolution Exhibits Funding Gastric Bypass Gatekeeping Gene Expression Gene Expression Profiling Genes Genomics Glucose Glycosylated hemoglobin A Goals HIF1A gene Health Hormonal Human Intake Intestinal Bypasses Intestines Link Longitudinal Studies Maps Masks Metabolic Metabolic Diseases Metabolism Molecular Nature Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Operative Surgical Procedures Organ Outcome Pathway Analysis Pathway interactions Patients Play Population Positioning Attribute Postoperative Period Procedures Published Comment Pyruvate Metabolism Pathway Research Research Proposals Resources Rodent Role Sampling Signal Pathway Signal Transduction Sirtuins Statistical Models Suggestion System Technology Testing Tissues United States United States National Institutes of Health Work bariatric surgery base biobank cell type clinical predictors clinically relevant effective therapy experimental study genetic signature glucose metabolism glycemic control health economics human subject improved insight novel obesity treatment operation organ on a chip predictive tools prospective public health relevance response single-cell RNA sequencing synergism tool transcriptomics

项目摘要

PROJECT SUMMARY Although Roux-en-Y Gastric Bypass (RYGB) is one of the most effective treatments for obesity and type 2 Diabetes Mellitus (T2DM), one out of three patients, still suffer from T2DM after the operation. Identifying those patients who do not achieve T2DM remission is important both mechanistically to help discover how RYGB improves glycemia, and clinically to initiate additional postoperative treatments early after surgery or to avoid the operation altogether. Studies in animal models and humans have emphasized the role of the intestine as a key anatomic substrate of the mechanisms of metabolic improvement after RYGB. The proposed project builds upon and expands the findings of our recent, prospective, longitudinal, observational clinical trial (ClinicalTrials.gov ID NCT02710370) the goal of which was to characterize the nature and the timing of RYGB- induced intestinal adaptive changes in humans. The three main implications that emerged from this trial were a) the enhancement of intestinal fuel utilization contributes in a significant and quantifiable manner to the 1- year postoperative decrement in HbA1c, positioning the gut as a key organ for RYGB-induced improved glycemia, b) the preoperative intestinal biology appears to be correlated with postoperative response, and thus this could be harnessed as a predictive clinical tool, and c) SIRT6-HIF1A pathway, a master gatekeeper of glucose metabolism linking energy substrate metabolism to function, appears to play a prominent role in the glycemic control of RYGB. The proposed project is a unique synergy between basic and clinical research teams and contains the requisite sophistication to further evaluate the role of augmented intestinal metabolism as one of the key mechanisms of action of RYGB and as a clinical tool to predict T2DM remission. We will perform 3 studies on human subjects. In Specific Aim 1, we will conduct a case control study to test the hypothesis that patients without T2DM remission post-RYGB exhibit a lower degree of intestinal metabolic activity and lower ability to engage SIRT6-HIF1A pathway effectively. In Specific Aim 2, we will conduct a prospective, longitudinal study to test whether specific composite metrics that take into account the preoperative gene expression levels could help predict postoperative HbA1c change, alone or in combination with other clinical, metabolic or hormonal factors. In Specific Aim 3, we will perform single cell RNA- Sequencing in biopsies from subjects before and after RYGB. These studies will further clarify the role of intestinal metabolism and the SIRT6-HIF1A pathway in RYGB-induced glycemic control. They will allow us to gain unprecedented insight into the intestinal cellular substrates, the regulatory networks and the mechanisms that are relevant for T2DM remission. They may also, potentially pave the way for the development of molecular predictors that could help guide clinical decisions for bariatric surgery candidates. Finally, they will generate unique resources, biobanks and datasets that will further enable mechanistic studies of intestinal biology and the mechanisms of action of bariatric surgery unobtainable to date.

项目概要尽管 Roux-en-Y 胃绕道术 (RYGB) 是治疗肥胖和 2 型肥胖最有效的方法之一糖尿病（T2DM），三分之一的患者在手术后仍然患有 T2DM。识别那些未达到 T2DM 缓解的患者在机制上对于帮助发现 RYGB 是如何发挥重要作用的改善血糖，临床上在手术后尽早开始额外的术后治疗或避免整个操作。对动物模型和人类的研究强调了肠道作为肠道的作用。 RYGB 后代谢改善机制的关键解剖学基础。拟建项目基于并扩展了我们最近的前瞻性、纵向、观察性临床试验的结果（ClinicalTrials.gov ID NCT02710370）其目标是描述 RYGB 的性质和时间安排- 诱导人类肠道适应性变化。该试验产生的三个主要影响是 a) 肠道燃料利用率的提高以显着且可量化的方式促进 1- 术后一年 HbA1c 下降，将肠道定位为 RYGB 诱导改善的关键器官血糖，b) 术前肠道生物学似乎与术后反应相关，因此这可以用作预测临床工具，并且 c) SIRT6-HIF1A 通路，一个主要的看门人葡萄糖代谢将能量底物代谢与功能联系起来，似乎在 RYGB 的血糖控制。拟议的项目是基础研究和临床研究之间的独特协同作用团队并包含必要的复杂性，以进一步评估增强肠道代谢的作用作为 RYGB 的关键作用机制之一，也是预测 T2DM 缓解的临床工具。我们将对人类受试者进行 3 项研究。在具体目标 1 中，我们将进行病例对照研究来测试假设 RYGB 后 T2DM 未缓解的患者表现出较低程度的肠道代谢活性和有效参与 SIRT6-HIF1A 通路的能力较低。在具体目标 2 中，我们将开展前瞻性、纵向研究，以测试是否考虑到特定的综合指标术前基因表达水平可以单独或组合帮助预测术后 HbA1c 变化与其他临床、代谢或激素因素。在具体目标 3 中，我们将进行单细胞 RNA- 对 RYGB 之前和之后受试者的活检进行测序。这些研究将进一步明确其作用肠道代谢和 SIRT6-HIF1A 通路在 RYGB 诱导的血糖控制中的作用。他们将使我们能够获得对肠道细胞底物、调节网络和机制的前所未有的了解与 T2DM 缓解相关。它们还可能为以下领域的发展铺平道路：分子预测因子可以帮助指导减肥手术候选者的临床决策。最后，他们将生成独特的资源、生物库和数据集，进一步促进肠道机制研究迄今为止还无法获得减肥手术的生物学和作用机制。